Priority Information
This application claims priority benefits under 35 U.S.C. § 119 to Japanese Patent Application No. P2003-062823, filed Mar. 10, 2003, and to Japanese Patent Application No. P2003-302803, filed on Aug. 27, 2003. The entire teachings of the above applications are incorporated herein by reference.
1. Field of the Invention
The present invention relates to a c-Kit kinase inhibitor, a therapeutic agent for a disease caused by the excessive activation of c-Kit kinase comprising c-Kit kinase inhibitor as an active ingredient.
2. Related Background of the Invention
Intracellular signal transduction by receptor tyrosine kinase contributes to cell proliferation, differentiation and metabolism; as a result, it is responsible for various diseases including cancers (Kolibaba K. S. et al., B.B.A. 1333, F217-F248, 1997; and Sheijen B. et al. Oncogene 21, 3314-3333, 2002).
c-Kit kinase, one of receptor tyrosine kinase, binds to SCF (stem cell factor) which is a ligand specific for the kinase. This causes dimerization of the kinase itself and the subsequent activation of the kinase activity. Consequently, a variety of substrates of c-Kit kinase in cells will be phosphorylated (Blume-Jensen P. et al., EMBO J. 10, 4121-4128, 1991; and Lev S. et al., EMBO J., 10, 647-654, 1991).
The abnormal activation of c-Kit kinase generates a proliferation signal in certain types of cancer cells (their representatives are described below), which is regarded as the cause of cancerization or malignant transformation.
(1) Acute myelogenous leukemia (AML): The expression of c-Kit kinase was found in a number of patients (60-80%) suffering from acute myelogenous leukemia and the proliferation of blast derived from the patients was stimulated by SCF. Furthermore, in 13 out of 18 patients the activation of c-Kit kinase was observed without SCF stimulation. It was then thought that activating mutations of c-Kit kinase occurred in these patients (Lev S. et al., EMBO J., 10, 647-654, 1991; Wang C et al., Leukemia 3, 699-702, 1989; Kanakura Y. et al., Leuk. Lymph. 10, 35-41, 1993; Ikeda H. et al., Blood, 78, 2962-2968, 1991; and Ikeda H. et al., Exp. Hematol. 21, 1686-1694, 1993).
(2) Mast cell leukemia: There was a report that activating mutations of c-Kit kinase was found in the cell line of mast cell leukemia a mastocytosis patient had developed (Furitsu T. et al., J. Clin. Invest., 92, 1736-1744, 1993).
(3) Small cell lung cancer (SCLC): While high level expression of c-Kit kinase was observed in more than 70% of SCLC cell lines, the expression levels of c-Kit kinase in the cell lines of non-small cell lung cancers were either low or below the detection limit. SCF, a ligand for c-Kit kinase, is also expressed in the cell lines of SCLC. This suggested the possibility that autocrine proliferation was promoted (Hibi K. et al., Oncogene, 6, 2291-2296, 1991; and Sekido Y. et al., Cancer Res., 51, 2416-2419, 1991).
(4) GIST (gastrointestinal stromal tumors): GIST is defined as a stromal tumor that develops in the GI tract expressing c-Kit kinase. In about a half of GIST, activating mutations of c-Kit kinase was found and it was present at high frequency in GIST with high malignancy. This suggested the possibility of the mutation being a prognosis factor (Lasota J. et al., Am. J. Pathol., 157, 1091-1095, 2000; and Taniguchi M. et al., Cancer Res., 59, 4297-4300, 1999).
(5) Testicular cancer: In testicular cancer, carcinoma in situ (CIS), which is regarded as a precancerous lesion, progresses to form tumors which are referred to as “seminoma” and “non-seminoma.” High-level expression of c-Kit kinase in CIS and seminoma was reported (Stromeyer T. et al., Cancer Res., 51, 1811-1816, 1991). In recent years there has been a report on the expression of c-Kit kinase that underwent an activating mutation in seminoma (Tian Q. et al., Am. J. Pathol., 154, 1643-1647, 1999).
(6) Ovarian cancer: There has been reported as follows. In normal ovarian epithelia, SCF was expressed but the expression of c-Kit kinase was not observed. However, c-Kit kinase and SCF were both expressed in benign ovarian tumor at an early stage of cancerization; oppositely, the expression of c-Kit kinase was lowered in malignant ovarian tumor. These results suggested that c-Kit kinase played an important role in the development of ovarian cancer (Tonary A. T., Int. J. Cancer, 89, 242-250, 2000).
(7) Breast cancer: There was a report that the expression of c-Kit kinase was lowered in breast cancer as compared to the surrounding normal tissues (Natali P. et al., Int. J. Cancer, 52, 713-717, 1992). However, in later studies the expression of c-Kit kinase, which had not been detected in normal tissue, was observed in breast cancer and SCF expression was also detected. These suggested that the autocrine stimulation promoted proliferation (Hines S. J. et al., Cell Growth & Differentiation, 6, 769-779, 1995).
(8) Brain cancer: There has been reported as follows: c-Kit kinase expression was observed in the cell line and tissue of glioblastoma that had the highest level of malignancy among brain cancers; and in the glioblastoma cell line expressing c-Kit kinase SCF stimulation promoted growth (Berdel W. E. et al., Cancer Res., 52, 3498-3502, 1992).
(9) Neuroblastoma: There has been reported as follows. SCF and c-Kit kinase were coexpressed in many cases of the cell lines and the tissue specimens of neuroblastoma which was well known as the cancer that developed in infants. Anti-c-Kit kinase antibody suppressed the growth of the cell line of neuroblastoma, and thus, growth was promoted by an autocrine mechanism (Cohen P. S., Blood, 84, 3465-3472, 1994).
(10) Colorectal cancer: Coexpression of c-Kit kinase and its ligand, SCF, was observed in a colorectal cancer tissue, whereas the expression of neither one was observed in a normal mucosal tissue. SCF stimulation promoted proliferation of the colorectal cancer cell line (Bellone G. et al., J. Cell. Physiol., 172, 1-11, 1997).
It was reported that the activation of c-Kit kinase by SCF stimulation was essential to proliferation and differentiation of mast cells (Hamel et al., J. Neuro-Onc., 35, 327-333, 1997; and Kitamura et al., Int. Arch. Aller. Immunol., 107, 54-56, 1995). It has, therefore, been thought that the excessive activation of c-Kit kinase is responsible for immunological abnormalities (such as mastocytosis, asthma and chronic rhinitis) which are caused by the excessive mast cells.
(1) Mastocytosis: Mastocytosis is a general term for the pathology of various conditions characterized by the excessive growth of mast cells (Metcalf, J. Invest. Derm. 93, 2S-4S, 1991; and Golkar et al., Lancet, 349, 1379-1385, 1997). The following have been reported on mastocytosis patients: 1) the excessive expression of c-Kit kinase (Nagata et al., Mastocytosis Leuk., 12, 175-181, 1998); 2) an increase in the amount of soluble SCF (Longley et al., New Engl. J. Med., 328, 1302-1307, 1993); and 3) activating mutations of c-Kit kinase (Nagata et al., Mastocytosis Leuk., 12, 175-181, 1998; and Longley et al., Nat. Gen., 12, 312-314, 1996). These are believed to excessively activate c-Kit kinase and thus to cause mastocytosis.
(2) Allergy and asthma: Mast cells and eosinophils are important cells in the development of inflammation, allergy, asthma and the like (Thomas et al., Gen. Pharmacol., 27, 593-597, 1996; and Metcalf et al., Physiol. Rev., 77, 1033-1079, 1997). This is suggested by the report that corticosteroids which are currently believed to be most effective against inflammations involving chronic rhinitis or allergy decrease the numbers of circuiting and invading mast cells and eosinophils (Naclerio et al., JAMA, 278, 1842-1848, 1997; and Meltzer, Aller., 52, 33-40, 1997). The activation of c-Kit kinase resulting from SCF stimulation was not only essential to differentiation, survival and proliferation of mast cells, but also promoted the induction of various factors from the mast cells. These factors fulfilled an important function in differentiation, survival and invasiveness of the eosinophils (Okayama et al., Int. Arch. Aller. Immunol., 114, 75-77, 1997; Okayama et al., Eur. J. Immunol., 28, 708-715, 1998; Metcalf et al., Proc. Natl. Acad. Sci., 95, 6408-6421, 1998; Kay et al., Int. Arch. Aller. Immunol., 113, 196-199, 1997; Hogaboam et al., J. Immunol. 160, 6166-6171, 1998; and Luckas et al., J. Immunol. 156, 3945-3951, 1996). It has, therefore, been thought that the inhibition of c-Kit kinase can suppress the activated mast cells and eosinophils in the patients suffering from asthma or allergy.
As stated above, c-Kit kinase is believed to be closely involved in the development or the malignant transformation of some types of cancers as well as in the diseases for which excessive mast cells are regarded as the cause. Inhibitors of c-Kit kinase have been considered useful as therapeutic agents for those diseases.